Sustained Release of Human Adipose Tissue Stem Cell Secretome from Star‐Shaped Poly(ethylene glycol) Glycosaminoglycan Hydrogels Promotes Motor Improvements after Complete Transection in Spinal Cord Injury Rat Model

Abstract Adipose tissue‐derived stem cells (ASCs) have been shown to assist regenerative processes after spinal cord injury (SCI) through their secretome, which promotes several regenerative mechanisms, such as inducing axonal growth, reducing inflammation, promoting cell survival, and vascular remodeling, thus ultimately leading to functional recovery. However, while systemic delivery (e.g., i.v. [intravenous]) may cause off‐target effects in different organs, the local administration has low efficiency due to fast clearance by body fluids. Herein, a delivery system for human ASCs secretome based on a hydrogel formed of star‐shaped poly(ethylene glycol) (starPEG) and the glycosaminoglycan heparin (Hep) that is suitable to continuously release pro‐regenerative signaling mediators such as interleukin (IL)‐4, IL‐6, brain‐derived neurotrophic factor, glial‐cell neurotrophic factor, and beta‐nerve growth factor over 10 days, is reported. The released secretome is shown to induce differentiation of human neural progenitor cells and neurite outgrowth in organotypic spinal cord slices. In a complete transection SCI rat model, the secretome‐loaded hydrogel significantly improves motor function by reducing the percentage of ameboid microglia and systemically elevates levels of anti‐inflammatory cytokines. Delivery of ASC‐derived secretome from starPEG‐Hep hydrogels may therefore offer unprecedented options for regenerative therapy of SCI.